This invention relates to novel quinazoline derivatives effective to induce apoptosis of brain tumor cells. In particular, the invention includes novel hydroxy quinazoline derivatives having potent cytotoxicity against human brain tumor cells, including glioblastoma. The novel compounds of the invention further inhibit adhesion of brain tumor cells to extracellular matrix proteins and inhibit migration of brain tumor cells through the extracellular matrix, activities required for tumor metastases.
As the most malignant primary central nervous systems tumors, high grade anaplastic astrocytoma and glioblastoma multiforme respond poorly to contemporary multimodality treatment programs employing surgical resection, radiation therapy and chemotherapy with a median survival of less than one year after initial diagnosis (Pardos, et al., 1997, Cancer Medicine, 1:1471-1514; Brandes, et al., 1996, Cancer Invest. 14:551-559; Finlay, J. L., 1992, Pediatric Neuro-Oncology, 278-297; Pardos, et al., 1998, Sem. Surgical Oncol., 14:88-95). Consequently, the development of effective new agents and novel treatment modalities against these very poor prognosis brain tumors remains a major focal point in translational oncology research.
Glioblastoma multiforme is also a highly invasive primary brain tumor with a disappointingly high local recurrence rate and mortality. New agents capable of inhibiting the infiltration of normal brain parenchyma by glioblastoma cells are urgently needed.
In a systematic effort to identify a cytotoxic agent with potent anti-tumor activity against glioblastoma cells, several hydroxy-substituted quinazoline-derivatives were synthesized and examined for their in vitro and in vivo effects on human glioblastoma cells. Novel hydroxy- and halo-hydroxy-quinazoline derivatives were found to exhibit potent cytotoxic activity against human glioblastoma cells at micromolar concentrations. Targeting of these compounds to the surface of brain tumor cells, for example, by conjugating hydroxy- and the halo-hydroxy compounds to a targeting moiety such as epidermal growth factor (EGF), further enhanced the cytotoxic activity (at nanomolar concentrations) The conjugate demonstrated more rapid and more potent anti-brain tumor activity, including apoptotic death of glioblastoma cells in vitro, significantly improved tumor-free survival in an in vivo SCID mouse glioblastoma xenograft model, inhibition of tumor cell adhesion to ECM proteins, and inhibition of tumor cell migration and invasion activity.
Accordingly, the present invention includes novel compounds and compositions having potent cytotoxic activity against brain tumor cells. Compositions of the invention contain an effective cytotoxic or inhibitory amount of a hydroxy-substituted quinozaline compound, more particularly of a hydroxy- or halo-hydroxy-substituted quinazoline derivative. The compounds of the invention include those having the following formula: 
where X is HN, R11N, S, O, CH2, or R11CH, and one or more of R1, R2, R3, R4, R5 is OH, SH, or NH2. Preferred embodiments include those where X is HN; R3 is OH; R2 and/or R4 is a halogen, preferably Br. In another preferred embodiment, one or more of R1-R5 form a second ring fused to the phenyl ring, for example, forming a napthyl ring and having at least one hydroxy substitution.
Preferred cytotoxic compounds of the invention include 4-(3xe2x80x2-Bromo-4xe2x80x2-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline[WHI-P154], 4-(4xe2x80x2-Hydroxylphenyl)-amino-6,7-dimethoxyquinazoline[WHI-P131], and 4-(2xe2x80x2-Hydroxy-naphthyl-3xe2x80x2)-amino-6,7-dimethoxyquinazoline[WHI-P292].
The compounds of the invention can be formulated for delivery to a subject as a pharmaceutical composition, and can preferably be modified for selective killing of brain tumor cells by conjugation to a cell specific targeting moiety, such as an anti-cell surface antigen-antibody, or a moiety known to bind a cell surface receptor, such as EGF. The compounds of the invention are preferably covalently bonded to the targeting moiety. One exemplary targeting moiety is EGF, which, when conjugated to the compound of the invention, rapidly and specifically directs the compound to brain tumor cells expressing the EGF receptor, resulting in specific, rapid, and enhanced cytoxicity.
The compounds of the invention are administered to a subject to inhibit the growth of brain tumor cells, to induce apoptosis of brain tumor cells, thereby reducing tumor mass. Compounds of the invention are also administered to inhibit the adhesion and migration of brain tumor cells, for example, inhibiting the infiltration of normal brain parenchyma by glioblastoma cells.